Drug eluting stent

ABSTRACT

An intraluminal stent comprising fibrin and an elutable drug is capable of providing a treatment of restenosis.

This is a divisional of application Ser. No. 08/306,785 filed on Sep.15, 1994, now U.S. Pat. No. 5,599,352 which is a continuation-in-part ofSer. No. 08/079,222 filed Jun. 17, 1993 now pending, which is acontinuation of Ser. No. 07/854,118 filed Mar. 19, 1992, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a method for lessening restenosis of bodylumens and to intraluminal stents having anti-thrombosis andanti-restenosis properties.

Restenosis is the reclosure of a peripheral or coronary artery followingtrauma to that artery caused by efforts to open a stenosed portion ofthe artery, such as, for example, by balloon dilation, ablation,atherectomy or laser treatment of the artery. For these angioplastyprocedures, restenosis occurs at a rate of about 20-50% depending on thedefinition, vessel location, lesion length and a number of othermorphological and clinical variables. Restenosis is believed to be anatural healing reaction to the injury of the arterial wall that iscaused by angioplasty procedures. The healing reaction begins with thethrombotic mechanism at the site of the injury. The final result of thecomplex steps of the healing process can be intimal hyperplasia, theuncontrolled migration and proliferation of medial smooth muscle cells,combined with their extracellular matrix production, until the artery isagain stenosed or occluded.

In an attempt to prevent restenosis, metallic intravascular stents havebeen permanently implanted in coronary or peripheral vessels. The stentis typically inserted by catheter into a vascular lumen and expandedinto contact with the diseased portion of the arterial wall, therebyproviding mechanical support for the lumen. However, it has been foundthat restenosis can still occur with such stents in place. Also, thestent itself can cause undesirable local thrombosis. To address theproblem of thrombosis, persons receiving stents also receive extensivesystemic treatment with anticoagulant and antiplatelet drugs.

To address the restenosis problem, it has been proposed to providestents which are seeded with endothelial cells (Dichek, D. A. et alSeeding of Intravascular Stents With Genetically Engineered EndothelialCells; Circulation 1989; 80: 1347-1353). In that experiment, sheependothelial cells that had undergone retrovirus-mediated gene transferfor either bacterial beta-galactosidase or human tissue-type plasminogenactivator were seeded onto stainless steel stents and grown until thestents were covered. The cells were therefore able to be delivered tothe vascular wall where they could provide therapeutic proteins. Othermethods of providing therapeutic substances to the vascular wall bymeans of stents have also been proposed such as in international patentapplication WO 91/12779 "Intraluminal Drug Eluting Prosthesis" andinternational patent application WO 90/13332 "Stent With Sustained DrugDelivery". In those applications, it is suggested that antiplateletagents, anticoagulant agents, antimicrobial agents, anti-inflammatoryagents, antimetabolic agents and other drugs could be supplied in stentsto reduce the incidence of restenosis. Further, other vasoreactiveagents such as nitric oxide releasing agents could also be used.

In the vascular graft art, it has been noted that fibrin can be used toproduce a biocompatible surface. For example, in an article by Soldaniet al., "Bioartificial Polymeric Materials Obtained from Blends ofSynthetic Polymers with Fibrin and Collagen" International Journal ofArtificial Organs, Vol. 14, No. 5, 1991, polyurethane is combined withfibrinogen and cross-linked with thrombin and then made into vasculargrafts. In vivo tests of the vascular grafts reported in the articleindicated that the fibrin facilitated tissue ingrowth and was rapidlydegraded and reabsorbed. Also, a published European Patent Application0366564 applied for by Terumo Kabushiki Kaisha, Tokyo, Japan, disclosesa medical device such as an artificial blood vessel, catheter orartificial internal organ which is made from a polymerized protein suchas fibrin. The fibrin is said to be highly nonthrombogenic and tissuecompatible and promotes the uniform propagation of cells that regeneratethe intima. Also, in an article by Gusti et al., "New Biolized Polymersfor Cardiovascular Applications", Life Support Systems, Vol. 3, Suppl.1, 1986, "biolized" polymers were made by mixing synthetic polymers withfibrinogen and cross-linking them with thrombin to improve tissueingrowth and neointima formation as the fibrin biodegrades. Also, in anarticle by Haverich et al., "Evaluation of Fibrin Seal in AnimalExperiments", Thoracic Cardiovascular Surgeon, Vol. 30, No. 4, pp.215-22, 1982, the authors report the successful sealing of vasculargrafts with fibrin. In the copending application Ser. No. 08/079,222, itis disclosed that the problem of restenosis can be addressed by the useof fibrin in an intravascular stent. However, it would be desirable toprovide a fibrin-based stent in which the stent also has a drug deliverycapability that would allow drugs to be delivered locally to the site ofa potential restenosis and then elute over a period of days to treat theblood vessel in the initial stages of restenosis and thereby prevent orlimit restenosis.

SUMMARY OF THE INVENTION

These and other objects of the invention have been achieved by thepresent invention. An intraluminal stent comprising fibrin can provide asuitable device to administer drugs for treatment of restenosis. Fibrinis a naturally occurring bioabsorbable polymer of fibrinogen that arisesduring blood coagulation. As set forth above, providing fibrin at thesite of treatment can provide a readily tolerated, bioabsorbable surfacewhich will interact in a natural manner with the body's healingmechanism and reduce the prospect for the intimal hyperplasia thatcauses restenosis. Local administration of drugs via the fibrin matrixof the stent can further reduce the prospect of restenosis. Asignificant problem in this regard is how to provide a therapeuticallyuseful amount of a substance in a relatively small fibrin stent.

To accomplish this while not affecting the strength of the overallfibrin stent structure, a first layer is applied to a stent body, thefirst layer incorporating a polymer and the therapeutic substance. Thefirst layer is then overcoated with a second layer including fibrinwhich includes little or none of the therapeutic agent.

In one embodiment of the invention, a solution which includes a solvent,a polymer dissolved in the solvent and a therapeutic drug dispersed inthe solvent is applied to the structural elements of the stent and thenthe solvent is evaporated. Fibrin can then be added over the coatedstructural elements. The inclusion of a polymer in intimate contact witha drug on the underlying stent structure allows the drug to be retainedon the stent in a resilient matrix during expansion of the stent andalso slows the administration of drug following implantation. The methodcan be applied whether the stent has a metallic or polymeric surface.The method is also an extremely simple method since it can be applied bysimply immersing the stent into the solution or by spraying the solutiononto the stent. The amount of drug to be included on the stent can bereadily controlled by applying multiple thin coats of the solution whileallowing it to dry between coats. The overall coating should be thinenough so that it will not significantly increase the profile of thestent for intravascular delivery by catheter. It is therefore preferablyless than about 0.002 inch thick and most preferably less than 0.001inch thick. The adhesion of the coating and the rate at which the drugis delivered can be controlled by the selection of an appropriatebioabsorbable or biostable polymer and by the ratio of drug to polymerin the solution. By this method, drugs such as glucocorticoids (e.g.dexamethasone, betamethasone), heparin, hirudin, tocopherol,angiopeptin, aspirin, ACE inhibitors, growth factors, oligonucleotides,and, more generally, antiplatelet agents, anticoagulant agents,antimitotic agents, antioxidants, antimetabolite agents, andanti-inflammatory agents can be applied to a stent, retained on a stentduring expansion of the stent and elute the drug at a controlled rate.The release rate can be further controlled by varying the ratio of drugto polymer in the multiple layers.

In another embodiment of the invention, the polymer in the first layeris fibrin. The coating of polymer and drug on the stent is achieved byforming a first fibrin layer on the stent body by applying fibrinogenand thrombin to the stent; while the fibrin layer is polymerizing,applying a layer of a therapeutic substance to the polymerizing fibrinlayer; and overcoating the therapeutic substance and fibrin with asecond fibrin layer. Alternatively, the therapeutic substance can bedispersed in a solution of fibrinogen which is applied to a stent bodyand thrombin can then be added in order to effect polymerization of thefibrinogen and to provide a fibrin matrix to contain the therapeuticsubstance. According to this method the amount of therapeutic substanceto be delivered by the stent can be controlled by employing multiplelayers of fibrin and therapeutic substance.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an elevational view of a balloon catheter with a metallicstent including a fibrin coating according to the present invention.

FIG. 2 is an elevational view of a balloon catheter with a metallicstent including a fibrin film according to the present invention.

FIG. 3 is an elevational view of a polymeric stent incorporating fibrinaccording to the present invention.

FIGS. 4-10 illustrate a method of making a stent according to thepresent invention. FIG. 4 is an elevational view of a stent and rigidtube into which the stent is inserted.

FIG. 5 is an elevational view of the tube of FIG. 4 into which acatheter balloon is inserted.

FIG. 6 is partial sectional view of the tube of FIG. 5 with includedstent and catheter.

FIG. 7 is a partial sectional view of the tube of FIG. 6 to which fibrinhas been added.

FIG. 8 is a partial sectional view of the tube of FIG. 7 in which theballoon has been expanded.

FIG. 9 is an elevational view of the resulting stent being removed fromthe tube of FIG. 8.

FIG. 10 is an elevational view of the completed stent mounted on theballoon of a catheter.

FIG. 11 is a top plan view of a multi-cavity mold for making a stentaccording to the invention.

FIG. 12 is an elevational view of the mold of FIG. 11.

FIG. 13 is an elevational view of the mold of FIG. 12 with the top moldhalves removed.

FIG. 14 is a flowchart of a process for making a fibrin stent using themulti-cavity mold of FIGS. 11 and 12.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a stent comprising fibrin. The term"fibrin" herein means the naturally occurring polymer of fibrinogen thatarises during blood coagulation.

Blood coagulation generally requires the participation of several plasmaprotein coagulation factors: factors XII, XI, IX, X, VIII, VII, V, XIII,prothrombin, and fibrinogen, in addition to tissue factor (factor III),kallikrein, high molecular weight kininogen, Ca⁺², and phospholipid. Thefinal event is the formation of an insoluble, cross-linked polymer,fibrin, generated by the action of thrombin on fibrinogen. Fibrinogenhas three pairs of polypeptide chains (ALPHA 2 - BETA 2 - GAMMA 2)covalently linked by disulfide bonds with a total molecular weight ofabout 340,000. Fibrinogen is converted to fibrin through proteolysis bythrombin. An activation peptide, fibrinopeptide A (human) is cleavedfrom the amino-terminus of each ALPHA chain; fibrinopeptide B (human)from the amino-terminus of each BETA chain. The resulting monomerspontaneously polymerizes to a fibrin gel. Further stabilization of thefibrin polymer to an insoluble, mechanically strong form, requirescross-linking by factor XIII. Factor XIII is converted to XIIIa bythrombin in the presence of Ca⁺². XIIIa cross-links the GAMMA chains offibrin by transglutaminase activity, forming EPSILON-(GAMMA-glutamyl)lysine cross-links. The ALPHA chains of fibrin also may be secondarilycross-linked by transamidation.

Since fibrin blood clots are naturally subject to fibrinolysis as partof the body's repair mechanism, implanted fibrin can be rapidlybiodegraded. Plasminogen is a circulating plasma protein that isadsorbed onto the surface of the fibrin polymer. The adsorbedplasminogen is converted to plasmin by plasminogen activator releasedfrom the vascular endothelium. The plasmin will then break down thefibrin into a collection of soluble peptide fragments.

Methods for making fibrin and forming it into implantable devices arewell known as set forth in the following patents and publishedapplications which are hereby incorporated by reference. In U.S. Pat.No. 4,548,736 issued to Muller et al., fibrin is clotted by contactingfibrinogen with a fibrinogen-coagulating protein such as thrombin,reptilase or ancrod. Preferably, the fibrin in the fibrin-containingstent of the present invention has Factor XIII and calcium presentduring clotting, as described in U.S. Pat. No. 3,523,807 issued toGerendas, or as described in published European Patent Application0366564, in order to improve the mechanical properties and biostabilityof the implanted device. Also preferably, the fibrinogen and thrombinused to make fibrin in the present invention are from the same animal orhuman species as that in which the stent of the present invention willbe implanted in order to avoid cross-species immune reactions. Theresulting fibrin can also be subjected to heat treatment at about 150°C. for 2 hours in order to reduce or eliminate antigenicity. In theMuller patent, the fibrin product is in the form of a fine fibrin filmproduced by casting the combined fibrinogen and thrombin in a film andthen removing moisture from the film osmotically through a moisturepermeable membrane. In the European Patent Application 0366564, asubstrate (preferably having high porosity or high affinity for eitherthrombin or fibrinogen) is contacted with a fibrinogen solution and witha thrombin solution. The result is a fibrin layer formed bypolymerization of fibrinogen on the surface of the device. Multiplelayers of fibrin applied by this method could provide a fibrin layer ofany desired thickness. Or, as in the Gerendas patent, the fibrin canfirst be clotted and then ground into a powder which is mixed with waterand stamped into a desired shape in a heated mold. Increased stabilitycan also be achieved in the shaped fibrin by contacting the fibrin witha fixing agent such as glutaraldehyde or formaldehyde. These and othermethods known by those skilled in the art for making and forming fibrinmay be used in the present invention.

Preferably, the fibrinogen used to make the fibrin is a bacteria-freeand virus-free fibrinogen such as that described in U.S. Pat. No.4,540,573 to Neurath et al which is hereby incorporated by reference.The fibrinogen is used in solution with a concentration between about 10and 50 mg/ml and with a pH of about 5.8-9.0 and with an ionic strengthof about 0.05 to 0.45. The fibrinogen solution also typically containsproteins and enzymes such as albumin, fibronectin (0-300 μg per mlfibrinogen), Factor XIII (0-20 μg per ml fibrinogen), plasminogen (0-210μg per ml fibrinogen), antiplasmin (0-61 μg per ml fibrinogen) andAntithrombin III (0-150 μg per ml fibrinogen). The thrombin solutionadded to make the fibrin is typically at a concentration of 1 to 120 NIHunits/ml with a preferred concentration of calcium ions between about0.02 and 0.2M.

Preferably the coagulating effect of any residual coagulation protein inthe fibrin should be neutralized before employing it in the stent of thepresent invention in order to prevent clotting at the fibrin interfacewith blood after stent implantation. This can be accomplished, forexample, by treating the fibrin with irreversible coagulation inhibitorcompounds or heat after polymerization. For example, hirudin orD-phenylalanyl-propyl-arginine chloromethyl ketone (PPACK) could beused. Anti-coagulants such as heparin can also be added to reduce thepossibility of further coagulation. To ensure the effectiveness of thetreatment with coagulation inhibitor or anti-coagulant it may bedesirable to apply such materials within 30 minutes before implantationof the device.

Polymeric materials can also be intermixed in a blend or co-polymer withthe fibrin to produce a material with the desired properties of fibrinwith improved structural strength. For example, the polyurethanematerial described in the article by Soldani et al., "BioartificialPolymeric Materials Obtained from Blends of Synthetic Polymers withFibrin and Collagen" International Journal of Artificial Organs, Vol.14, No. 5, 1991, which is incorporated herein by reference, could besprayed onto a suitable stent structure. Suitable polymers could also bebiodegradable polymers such as polyphosphate ester, polyhydroxybutyratevalerate, polyhydroxybutyrate-co-hydroxyvalerate and the like.

Also, the stent could be made with a porous polymeric sheet materialinto which fibrin is incorporated. Such a sheet material could be made,for example, as a polyurethane by dissolving a polyether urethane in anorganic solvent such as methyl-2-pyrrolidone; mixing into the resultingpolyurethane solution a crystalline, particulate material like salt orsugar that is not soluble in the solvent; casting the solution withparticulate material into a thin film; and then applying a secondsolvent, such as water, to dissolve and remove the particulate material,thereby leaving a porous sheet. The porous sheet could then be placedinto a fibrinogen solution in order to fill the pores with fibrinogenfollowed by application of a solution of thrombin and fibrinogen to thesurface of the sheet to establish a fibrin matrix that occupies both thesurface of the sheet and the pores of the sheet. Preferably, a vacuumwould be pulled on the sheet to insure that the fibrinogen applied tothe sheet is received into the pores.

The shape for the fibrin can be provided by molding processes. Forexample, the mixture can be formed into a stent having essentially thesame shape as the stent shown in U.S. Pat. No. 4,886,062 issued toWiktor. Unlike the method for making the stent disclosed in Wiktor whichis wound from a wire, the stent made with fibrin can be directly moldedinto the desired open-ended tubular shape.

In U.S. Pat. No. 4,548,736 issued to Muller et al., a dense fibrincomposition is disclosed which can be a bioabsorbable matrix fordelivery of drugs to a patient. Such a fibrin composition can also beused in the present invention by incorporating a drug or othertherapeutic substance useful in diagnosis or treatment of body lumens tothe fibrin provided on the stent. The drug, fibrin and stent can then bedelivered to the portion of the body lumen to be treated where the drugmay elute to affect the course of restenosis in surrounding luminaltissue. Examples of drugs that are thought to be useful in the treatmentof restenosis are disclosed in published international patentapplication WO 91/12779 "Intraluminal Drug Eluting Prosthesis" which isincorporated herein by reference. Therefore, useful drugs for treatmentof restenosis and drugs that can be incorporated in the fibrin and usedin the present invention can include drugs such as anticoagulant drugs,antiplatelet drugs, antimetabolite drugs, anti-inflammatory drugs andantimitotic drugs. Further, other vasoreactive agents such as nitricoxide releasing agents could also be used. Such therapeutic substancescan also be microencapsulated prior to their inclusion in the fibrin.The micro-capsules then control the rate at which the therapeuticsubstance is provided to the blood stream or the body lumen. This avoidsthe necessity for dehydrating the fibrin as set forth in Muller et al.,since a dense fibrin structure would not be required to contain thetherapeutic substance and limit the rate of delivery from the fibrin.For example, a suitable fibrin matrix for drug delivery can be made byadjusting the pH of the fibrinogen to below about pH 6.7 in a salinesolution to prevent precipitation (e.g., NaCl, CaCl, etc.), adding themicrocapsules, treating the fibrinogen with thrombin and mechanicallycompressing the resulting fibrin into a thin film. The microcapsuleswhich are suitable for use in this invention are well known. Forexample, the disclosures of U.S. Pat. Nos. 4,897,268, 4,675,189;4,542,025; 4,530,840; 4,389,330; 4,622,244; 4,464,317; and 4,943,449could be used and are incorporated herein by reference. Alternatively,in a method similar to that disclosed in U.S. Pat. No. 4,548,736 issuedto Muller et al., a dense fibrin composition suitable for drug deliverycan be made without the use of microcapsules by adding the drug directlyto the fibrin followed by compression of the fibrin into a sufficientlydense matrix that a desired elution rate for the drug is achieved. Inyet another method for incorporating drugs which allows the drug toelute at a controlled rate, a solution which includes a solvent, apolymer dissolved in the solvent and a therapeutic drug dispersed in thesolvent is applied to the structural elements of the stent and then thesolvent is evaporated. Fibrin can then be added over the coatedstructural elements in an adherent layer. The inclusion of a polymer inintimate contact with a drug on the underlying stent structure allowsthe drug to be retained on the stent in a resilient matrix duringexpansion of the stent and also slows the administration of drugfollowing implantation. The method can be applied whether the stent hasa metallic or polymeric surface. The method is also an extremely simplemethod since it can be applied by simply immersing the stent into thesolution or by spraying the solution onto the stent. The amount of drugto be included on the stent can be readily controlled by applyingmultiple thin coats of the solution while allowing it to dry betweencoats. The overall coating should be thin enough so that it will notsignificantly increase the profile of the stent for intravasculardelivery by catheter. It is therefore preferably less than about 0.002inch thick and most preferably less than 0.001 inch thick. The adhesionof the coating and the rate at which the drug is delivered can becontrolled by the selection of an appropriate bioabsorbable or biostablepolymer and by the ratio of drug to polymer in the solution. By thismethod, drugs such as glucocorticoids (e.g. dexamethasone,betamethasone), heparin, hirudin, tocopherol, angiopeptin, aspirin, ACEinhibitors, growth factors, oligonucleotides, and, more generally,antiplatelet agents, anticoagulant agents, antimitotic agents,antioxidants, antimetabolite agents, and anti-inflammatory agents can beapplied to a stent, retained on a stent during expansion of the stentand elute the drug at a controlled rate. The release rate can be furthercontrolled by varying the ratio of drug to polymer in the multiplelayers. For example, a higher drug-to-polymer ratio in the outer layersthan in the inner layers would result in a higher early dose which woulddecrease over time. Examples of some suitable combinations of polymer,solvent and therapeutic substance are set forth in Table 1 below.

                  TABLE 1                                                         ______________________________________                                        POLYMER    SOLVENT    THERAPEUTIC SUBSTANCE                                   ______________________________________                                        poly(L-lactic                                                                            chloroform dexamethasone                                           acid)                                                                         poly(lactic                                                                              acetone    dexamethasone                                           acid-co-                                                                      glycolic acid)                                                                polyether  N-methyl   tocopherol                                              urethane   pyrrolidone                                                                              (vitamin E)                                             silicone   xylene     dexamethasone                                           adhesive              phosphate                                               poly(hydroxy-                                                                            dichloro-  aspirin                                                 butyrate-co-                                                                             methane                                                            hydroxyvalerate)                                                              ______________________________________                                    

The polymer used can be a bioabsorbable or biostable polymer. Suitablebioabsorbable polymers include poly(L-lactic acid),poly(lactide-co-glycolide) and poly(hydroxybutyrate-co-valerate).Suitable biostable polymers include silicones, polyurethanes,polyesters, vinyl homopolymers and copolymers, acrylate homopolymers andcopolymers, polyethers and cellulosics. A typical ratio of drug todissolved polymer in the solution can vary widely (e.g. in the range ofabout 10:1 to 1:100). The fibrin is applied by molding a polymerizationmixture of fibrinogen and thrombin onto the composite as describedherein.

In another embodiment of the invention, the coating of polymer and drugon the stent is achieved by forming a first fibrin layer on the stentbody which incorporates the therapeutic substance and then applying asecond layer of fibrin. One way this may be accomplished is by applyingfibrinogen and thrombin to the stent; while the fibrin layer ispolymerizing, applying a layer of a therapeutic substance to the to thepolymerizing fibrin layer; and then overcoating the therapeuticsubstance and fibrin with a second fibrin layer. According to thismethod the amount of therapeutic substance to be delivered by the stentcan be controlled by employing multiple layers of fibrin and therapeuticsubstance. For example, to incorporate dexamethasone into a stent thestent body is first wetted with a fibrinogen solution (e.g. 5 mg/ml) andthen wetted with a thrombin solution (e.g. 12 NIH units/ml) in order toform fibrin on the stent surface. After about 2-3 minutes, while thesurface is still tacky, apply a known concentration of dexamethasonepowder to the tacky fibrin. This can be accomplished by any number ofmethods, including rolling or spraying the powder onto the fibrin. Afterabout 5 minutes at room temperature, the dexamethasone-coated stent isready to be coated with the second layer of fibrin. This can beaccomplished in a mold as described below. In yet another way thisembodiment of the invention can be carried out, a water dispersible (orsoluble) therapeutic substance is dispersed in the fibrinogen solutionand this solution is applied to a stent body. Thrombin is added topolymerize the fibrinogen on the stent body and thereby produce a fibrinwith a therapeutic substance incorporated in the fibrin matrix. Thefirst fibrin layer can then be provided with the second fibrin coating.

The term "stent" herein means any device which when placed into contactwith a site in the wall of a lumen to be treated, will also place fibrinat the lumen wall and retain it at the lumen wall. This can includeespecially devices delivered percutaneously to treat coronary arteryocclusions and to seal dissections or aneurysms of splenic, carotid,iliac and popliteal vessels. The stent can also have underlyingpolymeric or metallic structural elements onto which the fibrin isapplied or the stent can be a composite of fibrin intermixed with apolymer. For example, a deformable metal wire stent such as thatdisclosed in U.S. Pat. No. 4,886,062 issued to Wiktor could be coatedwith fibrin as set forth above in one or more coats (i.e polymerizationof fibrin on the metal framework by application of a fibrinogen solutionand a solution of a fibrinogen-coagulating protein) or provided with anattached fibrin preform such as an encircling film of fibrin made as setforth above (i.e a cast film as set forth in the Muller et al. patent).The stent and fibrin could then be placed onto the balloon at a distalend of a balloon catheter and delivered by conventional percutaneousmeans (e.g. as in an angioplasty procedure) to the site of therestriction or closure to be treated where it would then be expandedinto contact with the body lumen by inflating the balloon. The cathetercan then be withdrawn, leaving the fibrin stent of the present inventionin place at the treatment site. The stent may therefore provide both asupporting structure for the lumen at the site of treatment and also astructure supporting the secure placement of fibrin at the lumen wall.FIG. 1 shows a stent having this general construction in place on aballoon catheter. A catheter 10 has a balloon 15 upon which a stent 20has been placed, the stent 20 having a deformable metal portion 22 and afibrin coating 24 thereon. FIG. 2 shows an alternative stent 30 in whicha fibrin film 32 has been affixed to the underlying metallic framework34 by affixing it to the stent 30 by e.g. wrapping the film 32 aroundthe framework 34 and securing the film 32 to the framework 34 (i.e. thefilm is usually sufficiently tacky to adhere itself to the framework butan adhesive material could also be used if needed) so that the film 32will stay on the balloon 36 and framework 34 until it is delivered tothe site of treatment. The film 32 is preferably wrapped over theframework 34 with folds or wrinkles that will allow the stent 30 to bereadily expanded into contact with the wall of the lumen to be treated.

Also, for example, a self-expanding stent of resilient polymericmaterial such as that disclosed in published international patentapplication WO 91/12779 "Intraluminal Drug Eluting Prosthesis" could beused in which fibrin is coated onto the stent or incorporated within thepolymeric material of the stent. A stent of this general configurationis shown in FIG. 3. The stent 40 has a first set of filaments 42 whichare helically wound in one direction and a second set of filaments 44which are helically wound in a second direction. Any or all of thesefilaments 42, 44 could be fibrin and/or a blend of fibrin with anotherpolymer. The combination of fibrin with another polymer may be preferredto provide improved mechanical properties and manufacturability for theindividual filaments 42, 44. A suitable material for fibrin-containingfilaments 42, 44 is the crosslinked blend of polyurethane and fibrinused as a vascular graft material in the article by Soldani et al.,"Bioartificial Polymeric Materials Obtained from Blends of SyntheticPolymers with Fibrin and Collagen" International Journal of ArtificialOrgans, Vol. 14, No. 5, 1991, which is incorporated herein by reference.Other biostable or bioerodeable polymers could also be used. Afibrin-containing stent of this configuration can be affixed to thedistal end of a catheter in a longitudinally stretched condition whichcauses the stent to decrease in diameter. The stent is then deliveredthrough the body lumen on the catheter to the treatment site where thestent is released from the catheter to allow it to expand into contactwith the lumen wall. A specialized device for deploying such a stent isdisclosed in U.S. Pat. No. 5,192,297 issued to Hull. It will be apparentto those skilled in the art that other self-expanding stent designs(such as resilient metal stent designs) could also be used with fibrineither incorporated in the material of the underlying structure of thestent or filmed onto the underlying structure of the stent.

A preferred method of making a stent according to the present inventionis as set forth in FIGS. 4-10. A stent 50 of the type disclosed in U.S.Pat. No. 4,886,062 issued to Wiktor is inserted into a tube 55 which ispreferably made from a rigid material and which has an inside diameterwhich is large enough to accommodate an unexpanded PTCA balloon butwhich is smaller than a fully inflated PTCA balloon. A PTCA balloon 60attached to a catheter 62 and inflation device (not shown) is insertedinto the stent 50 and tube 55. Fibrinogen at a pH of about 6.5,suspended in a saline solution, and thrombin are inserted into the tube55 around the deflated balloon 60 and stent 50. The amount of thrombinadded is not critical but preferably will polymerize the fibrinogen tofibrin 65 in about 5 minutes. After polymerization, the fibrin isallowed to crosslink for at least an hour, preferably several hours. Theballoon 60 is then inflated to compress the fibrin 65 between theballoon 60 and tube 55. The balloon 60 is then deflated and removed fromthe tube 55. The resulting fibrin stent 70 includes the stent 50embedded in a very thin elastic film of fibrin 65. The fibrin stent 70may then be removed from the tube 55 and washed in a buffered salinesolution.

Further processing of the fibrin stent can also be undertaken toneutralize thrombin with PPACK or hirudin; to add anticoagulants such asheparin; to further facilitate crosslinking by incubation at bodytemperature in a biological buffer such as a solution of blood serumbuffered by 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES);or to add plasticizers such as glycerol. The resulting fibrin stent canthen be placed over a balloon, and secured onto the balloon by crimping.The stent can then be delivered transluminally and expanded into placein the body lumen by conventional procedures.

Preferably, heparin is incorporated into the stent prior to implantationin an amount effective to prevent or limit thrombosis. For example, thefibrin stent can be immersed in a solution of heparin within 10-30minutes prior to implantation. The heparin immersion procedure can beconducted in a heparin solution having a concentration of about1000-25,000 heparin units/ml. It may also be desirable to incorporateheparin into the fibrin matrix before it is completely polymerized. Forexample, after the fibrinogen and thrombin have been combined and theresulting fibrin has been shaped but within two hours of combining thefibrinogen and thrombin, the fibrin is immersed in a solution ofheparin. Since the fibrin polymerization is largely complete at thispoint, the fibrin can be immersed in heparin solution containing up toabout 20,000 units/ml of heparin without damaging the integrity of thefibrin structure. Immersion times will depend on the concentration ofthe heparin solution and the concentration of heparin desired in thefibrin. However, preferably, in a solution of heparin having aconcentration of about 10,000-20,000 units/ml of heparin, an immersiontime of about 12-24 hours may be used. In yet another method forincorporation of heparin in the fibrin, the heparin can be included inthe fibrinogen or in the initial mixture of fibrinogen and thrombin solong as the ratio of heparin to fibrinogen is such that the presence ofthe heparin does not lead to a weak fibrin film. Typically, less thanabout 50-500 units of heparin can be used in a stent which includes0.003-0.006 grams of fibrin. In yet another method for incorporatingheparin into the fibrin, powdered heparin can be dusted onto the stentduring the polymerization process and additional thrombin and fibrinogencan then be applied as a coating over the heparin.

The metal stent portion mentioned above may be eliminated to make afibrin tube which can be placed on a balloon catheter and expanded intoplace in a body lumen. The absence of permanently implanted metalelements would allow the entire stent to biodegrade as healing iscompleted in the body lumen. In order to achieve sufficient structuralsupport for a stent without a metal structure, it may be desirable toform supporting elements from elastin orelastin/fibrin/collagen/fibronectin as replacements for the metalsupporting elements. If desired, fibrin glue or fibrinogen can also beapplied to the exterior of the fibrin tube immediately prior to platingit into the blood vessel in order to improve its adhesion to the vesselwall.

In yet another method for making the fibrin stent, the fibrin can bepolymerized in a multi-cavity mold such as that shown in FIGS. 11 and12. The mold 100 is a three piece mold consisting of first and secondmold halves 101, 102 and mold base 103. A series of pins 105-108 andscrews 110-113 secure the mold pieces 101-103 together. As assembled,the mold halves 101, 102 define five mold cavities 115a-e. Centrallylocated within each of the mold cavities 115a-e is a corresponding pin117a-e which is retained in the mold base 103. In the mold base 103 is aseries of laterally extending air passageways 120a-e which communicatewith the cavities 115a-e to allow complete filling of the mold cavity.The molding surfaces are coated with a polymeric slip coating such asPTFE to permit the piece parts to be removed from the mold cavitiesafter curing. FIG. 13 shows the mold base 103 of FIG. 12 after the moldhalves 101, 102 have been removed following the molding operation. Pins117a-e are shown surrounded by the molded fibrin 121a-e.

Now referring also to FIG. 14, in operation, a stent 125 is placed intothe mold 100 into one of the mold cavities 115a such that the pin 117aoccupies the hollow center of the stent 125. A fibrinogen mixture withthrombin 130 is made by metering the fibrinogen solution and thrombinsolution into a sterile syringe and then moving the plunger of thesyringe to mix the solutions. For example, 0.5 ml of a fibrinogensolution having a concentration of 26 mg/ml can be mixed with 0.125 mlof a thrombin solution having a concentration of 12 NIH units/ml. Themixture 130 is then injected into the bottom of the cavity 115a of themold 100 to fill the cavity 115a and encompass the stent 125. Themixture 130 is then allowed to cure. With the mixture indicated above,the curing interval should be at least two hours. Once the mixture 130has clotted, sterile water may be applied by spraying onto the mold 100to prevent the fibrin from drying out. When cured, the molded preform140 comprising the stent 125 and the cured mixture 130 is removed fromthe mold 100 by removing the mold base 103 and pulling the moldedpreform 140 from the pin 117a. Since the pin 117 is coated with PTFE,the cured mixture 130 does not adhere to the pin 117a and the moldedpreform 140 can be removed by carefully pushing the preform from thebottom of pin 117a using a plastic tweezers. If required, excess fibrincan be trimmed from the preform 140 at this point or trimming can takeplace at a later stage of processing where the fibrin is stronger. Thepreform 140 can then be further crosslinked by treating it in a buffersolution 145 which may optionally contain crosslinking agents such asFactor XIIIa. For example, the buffer 145 could be a tris buffer with apH of 7.4 with the preform 140 immersed in the tris buffer for at leastfive hours. Preferably, a solution of heparin 135 is also included inthe mixture 130. The mixture 130 with heparin 135 is then injected intothe cavity 115a of the mold 100 and allowed to cure. Alternatively,immediately after the preform 140 is removed from the mold 100, thepreform 140 can be immersed in a heparin solution. After crosslinking,the preform 140 undergoes an additional molding stage in a cavity of asecond mold 150 in which pressure 155 is applied to provide the finalform of the fibrin stent 160. For example, the mold can simply be apolycarbonate tube and the preform 140 can be placed over the balloon ofa balloon catheter and into the tube. The balloon is then slowlyinflated causing the preform 140 to be pressed against the sides of thetube. The effect of the expansion and pressure on the fibrin is tostretch it and thin it because of the viscoelastic properties of thefibrin. Because fibrin is such a fragile material, it is important tocontrol the expansion by slow expansion to prevent the fibrin fromtearing and also to provide a stent with the proper dimensions forexpansion in vivo without tearing. For example, the preform 140 may havean internal diameter of about 2.7 mm and may be placed on a 3.5 mmballoon and into a mold 150 having a 3.4 mm internal diameter. Theballoon can then be expanded slowly at one atmosphere increments until apressure of about six atmospheres is achieved. Pressure 155 is thentypically maintained on the fibrin stent 160 inside the second mold 150for a short period of time in order to set the fibrin stent 160 into itsfinal shape. Typically thirty minutes at six atmospheres of pressure issufficient. Upon release of pressure in the balloon, the balloon andfibrin stent 160 can be withdrawn from the mold 150. If the fibrin stent160 is to be packaged and shipped dry, it can then be dehydrated 170 bywell known methods such as air drying, ethanol dehydration orlyophilization and packaged 180 for storage and use. Typically, afterpackaging 180, the fibrin stent 160 is sterilized 190 by gamma or E-beamsterilization. It will be readily appreciated that a fibrin stent withan attached metallic framework can be readily provided by this moldingmethod.

Sterilization of the fibrin stent can be accomplished by starting withsterile, virus-free materials and manufacturing the device under sterileprocessing conditions. The sterile processing conditions includemanufacturing the device under standard clean room conditions and endingthe manufacturing process with a final sterilization step. The finalsterilization step would expose the packaged device to radiation,preferably gamma radiation, at a level sufficient to cause disruption ofmicroorganism DNA. This can be accomplished at an approximately 2.5 MRadgamma ray dosage. A suitable gamma ray source can be e.g. cobalt-60 orcesium-137. Another suitable form of radiation can be electron beamradiation. The packaged device configuration at irradiation can beeither dry or wet--i.e. with the fibrin stent in the package in adehydrated state or in a wet pack package where the fibrin is maintainedin a 100% relative humidity environment until end use.

It will be appreciated by those skilled in the art that while theinvention has been described above in connection with particularembodiments the invention is not necessarily so limited and thatnumerous other embodiments, uses, modifications and departures from theembodiments, and uses may be made without departing from the inventiveconcepts.

We claim:
 1. A method for delivery of a therapeutic substance to theinterior of a body lumen comprising the steps of:(a) providing agenerally cylindrical stent body; (b) applying to the stent body a firstlayer which is a solid composite of polymer and therapeutic substance;(c) applying fibrin over the composite; (d) introducing the stenttransluminally into a selected portion of the body lumen; and (e)radially expanding the stent into contact with the body lumen.
 2. Themethod of claim 1 wherein the first layer is applied by the steps of:(a)applying to the stent body a solution which includes a solvent, apolymer dissolved in the solvent and a therapeutic substance dispersedin the solvent; and (b) evaporating the solvent to form a composite ofpolymer and therapeutic substance.
 3. The method of claim 2 wherein thesolution is applied by spraying.
 4. The method of claim 2 wherein thesolution is applied in a plurality of application and drying steps. 5.The method of claim 2 wherein a ratio of therapeutic substance todissolved polymer in the solution is varied in some of the plurality ofapplication steps.
 6. The method of claim 2 wherein the polymer is abioabsorbable polymer.
 7. The method of claim 6 wherein the polymer isselected from the group consisting of poly(L-lactic acid),poly(lactide-co-glycolide) and poly(hydroxybutyrate-co-valerate).
 8. Themethod of claim 2 wherein the polymer is a biostable polymer.
 9. Themethod of claim 8 wherein the polymer is selected from the groupconsisting of silicones, polyurethanes, polyesters, vinyl homopolymersand copolymers, acrylate homopolymers and copolymers, polyethers andcellulosics.
 10. The method of claim 1 wherein the first layer isapplied by the steps of:(a) applying to the stent body a solution whichincludes fibrinogen; (b) applying thrombin to the fibrinogen on thestent body to effect polymerization of the fibrinogen; and (c) applyinga therapeutic substance to the fibrinogen as the fibrinogen ispolymerizing.
 11. The method of claim 1 wherein the first layer isapplied by the steps of:(a) applying to the stent body a solution whichincludes fibrinogen and a dispersed therapeutic substance; and (b)applying thrombin to the fibrinogen on the stent body to effectpolymerization of the fibrinogen.
 12. The method of claim 1 wherein thetherapeutic substance is selected from the group consisting ofglucocorticoids, heparin, hirudin, tocopherol, angiopeptin, aspirin, ACEinhibitors, growth factors, oligonucleotides, antiplatelet agents,anticoagulant agents, antimitotic agents, antioxidants, antimetaboliteagents, and anti-inflammatory agents.
 13. The method of claim 1 whereinthe fibrin is applied by molding a polymerization mixture of fibrinogenand thrombin onto the composite.
 14. A method for delivery of atherapeutic substance to an interior of a body lumen comprising thesteps of:(a) providing a generally cylindrical stent having a body, saidbody having applied thereto a first layer which is a solid composite ofpolymer and therapeutic substance and a layer of fibrin as a secondlayer over the composite; (b) introducing the stent transluminally intoa selected portion of the body lumen; and (c) radially expanding thestent into contact with the body lumen.
 15. The method of claim 14wherein the polymer is a bioabsorbable polymer.
 16. The method of claim15 wherein the polymer is selected from the group consisting ofpoly(L-lactic acid), poly(lactide-co-glycolide) andpoly(hydroxybutyrate-co-valerate).
 17. The method of claim 14 whereinthe polymer is a biostable polymer.
 18. The method of claim 17 whereinthe polymer is selected from the group consisting of silicones,polyurethanes, polyesters, vinyl homopolymers and copolymers, acrylatehomopolymers and copolymers, polyethers and cellulosics.
 19. The methodof claim 14 wherein the therapeutic substance is selected from the groupconsisting of glucocorticoids, heparin, hirudin, tocopherol,angiopeptin, aspirin, ACE inhibitors, growth factors, oligonucleotides,antiplatelet agents, anticoagulant agents, antimitotic agents,antioxidants, antimetabolite agents, and anti-inflammatory agents.